Myocardial infarction (MI), or heart attack, is a disease due to interruption of the blood supply to a part of the heart, causing damage or death of heart muscle cells. It is the leading cause of death for both men and women over the world. Following myocardial infarction, there does not seem to be any natural occurring repairing process capable of generating new cardiomyocytes to replace the lost muscle cells. Instead, scar tissues may replace the necrosed myocardium, causing further deterioration in cardiac function.
Therapeutic replacement of the necrosed heart tissue with newly regenerated functional cardiac myocytes is a treatment ideal that until recently has been unrealistic, because cardiac myocytes were considered to be terminally differentiated, or in other words, the heart is a postmitotic nonregenerating organ. This dogma, however, has recently been challenged by Beltrami et al, and others, who reported that a population of resident myocytes within the myocardia can and do replicate after infarction. In order to promote and improve the repair for infarcted myocardia, transplantation of cardiomyocytes or skeletal myoblasts has been attempted, but has not been very successful in reconstituting functional myocardia and coronary vessels. Transplantation of adult bone marrow-derived mesenchymal stem cells (MSCs) for cardiac repair following myocardial infarction has resulted in some angiogenesis and myogenesis, but the location of the newly regenerated cardiac myocytes appeared mostly along the border zone where the blood supply is relatively less affected1-3.
Because acute myocardial infarction (MI) brings rapid damages or death to myocytes (heart muscle cells), vascular structures and nonvascular components in the supplied region of the ventricle, regeneration of new cardiac myocytes to replace the infarcted myocardia (heart muscular tissues) in the central infarcted zone (the absolute ischemic region) through a sub-population of cardiac myocyte growth4-8 or transplantation of MSCs1-3 alone appears to be impossible without early reestablishment of the blood supply network locally. This probably explains why regeneration of cardiac myocytes following MSCs transplantation alone occurred mostly along the border zone adjacent to the infarct where the blood supply is largely maintained1-11. Therefore, the loss of myocardia, arterioles and capillaries in the central infarct area appeared to be irreversible, eventually leading to scar formation.
A more recent study12 reported that heart transplantation of MSC pre-modified with exogenous Akt in vitro produced a better result. Nonetheless, the regenerated cardiac myocytes could only infiltrate from the border zone into the scarred area, indicating that overexpression of exogenous Akt, although enhancing the survival potential of the transplanted MSCs, itself is insufficient to enable them to survive in central ischemic regions. Furthermore, even in the less-ischemic border zones, it was noted that the MSCs-derived regenerating cardiac myocytes were scattered and seemed to have difficulty to cluster and form regenerating myocardia. This is probably due to poor cardiomyogenic differentiation efficiency of the survived transplanted MSCs. The knowledge that natural cardiomyocyte reproduction, including differentiation of residential progenitor myocytes or stem cells recruited from other sources, such as from endothelial cells or a niche in the bone marrow is insufficient to balance cardiomyocyte death occurred in acute or chronically damaged heart, has damped the enthusiasm of the researchers who thought myocardial regeneration would represent a promising method of treatment against heart diseases.
The prior art seems to teach that there are three major requirements critical for regenerating functional myocytes in the entire areas of infarcted myocardia: 1) increased viability of the transplanted cells so that they may survive through the absolute ischemic period, that is, the period from injection of the donor cells to formation of new vessels; 2) early reconstitution of the damaged blood supply network in the infarcted myocardia to sustain the survival and efficient trafficking of the transplanted cells and maintain oxygenation and nutrient delivery; and 3) enhanced cardiomyogenic differentiation efficiency of the transplanted cells to enable more survived donor cells to differentiate down cardiac linage.
Therefore, to realize the therapeutic ideal of replacing necrosed heart tissues with newly regenerated functional cardiac myocytes, there is a need for new therapeutic approaches, for example, an approach using chemical compounds possessing biological properties that sufficiently satisfy the aforementioned three requirements in order to serve the therapeutic needs for treating myocardial infarction.